Immunohistochemical analysis of the immune checkpoint molecule Galectin-9 in meningiomas
Year 2024,
Volume: 49 Issue: 3, 600 - 606, 30.09.2024
Ismail Saygin
,
Emel Çakır
,
Seher Nazlı Kazaz
,
Ali Rıza Güvercin
,
İlker Eyüboğlu
,
Müşerref Müge Ustaoğlu
Abstract
Purpose: Most meningiomas can be treated by surgical resection. However, depending on the location of the lesion, incomplete resection or high-grade meningiomas may have a poor prognosis. The new methods such as immunotherapy may improve our options for effective, patient-specific treatment of meningiomas. We aim to contribute to the development of new personalized treatment strategies by investigating the status of Gal-9 in meningiomas.
Materials and Methods: Four hundred two cases diagnosed in our laboratory between 2007 and 2020 were used for the study. New blocks of multiple tissues were prepared for immunohistochemistry using the tissue microarray method. Immunohistochemical staining of Gal-9 antibody was evaluated using the H-score method.
Results: Of the 402 cases studied, 289 were female and 113 were male. Two hundred and seventy-one (67.4%) cases were WHO grade 1; 121 (30.1%) were grade 2 and 10 (2.5%) were grade 3. A high H-score was observed in grade 1 and 2 tumors (H-score: 93.38 and 93.91) and a low H-score in grade 3 tumors (H-score: 59.40). There was no significant correlation between brain invasion and Gal-9 expression. No significant correlation was found between Gal-9 expression and minor criteria used in tumor grading.
Conclusion: A statistically significant difference was found between Gal-9 H-score and tumor grade. Gal-9 had a lower H-score in high-grade meningiomas and its expression level decreased. Therefore, Gal-9 with different expression levels can be used as a prognostic and predictive biomarker as well as an important molecule for treatment.
Ethical Statement
There are no conflicts of interest in connection with this paper, and the material described is not under publication or consideration for publication elsewhere.
Supporting Institution
The Scientific And Technological Research Council Of Turkey (TUBİTAK)
References
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- Al-Rashed M, Foshay K, Abedalthagafi M. Recent advances in meningioma immunogenetics. Front Oncol. 2020;9:1472.
- Moar P, Tandon R. Gal-9 as a biomarker of disease severity. Cell Immunol. 2021;361:104287.
- Torp SH, Solheim O, Skjulsvik AJ. The WHO 2021 Classification of central nervous system tumours: a practical update on what neurosurgeons need to know-a minireview. Acta Neurochir (Wien). 2022;164:2453-64.
- Gupta S, Bi WL, Dunn IF. Medical management of meningioma in the era of precision medicine. Neurosurg Focus. 2018;44:E3.
- Shahbandi A, Shah DS, Hadley CC, Patel AJ. The role of pharmacotherapy in treatment of meningioma: a systematic review. Cancers. 2023;12;15:483.
- Foy SP. Mandl SJ. Dela Cruz T et al. Poxvirus-based active immunotherapy synergizes with CTLA-4 blockade to increase survival in a murine tumor model by improving the magnitude and quality of cytotoxic T cells. Cancer Immunol Immunother. 2016;65:537‐49.
- Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T et al. Check point blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature. 2014;515:577‐81.
- Yang R, Sun L, Li CF, Wang YH, Xia W, Liu B et al. Development and characterization of anti-gal-9 antibodies that protect T cells from galectin-9-induced cell death. J Biol Chem. 2022;298:101821.
- Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ et al. The Tim-3 ligand gal-9 negatively regulates T helper type 1 immunity. Nat Immunol. 2005;6:1245-52.
- Liu Z, Han H, He X, Li S, Wu C, Yu C et al. Expression of the gal-9 Tim-3 pathway in glioma tissues is associated with the clinical manifestations of glioma. Oncol Lett. 2016;11:1829-34.
- Daley D, Mani VR, Mohan N, Akkad N, Ochi A, Heindel DW et al. Dectin 1 activation on macrophages by gal-9 promotes pancreatic carcinoma and peritumoral immune tolerance. Nat Med. 2017;23:556-67.
- Wu C, Thalhamer T, Franca RF, Xiao S, Wang C, Hotta C et al. Gal-9 - CD44 interaction enhances stability and function of adaptive regulatory T cells. Immunity. 2014;41:270-82.
- Madireddi S, Eun SY, Mehta AK, Birta A, Zajonc DM, Niki T et al. Regulatory t cell-mediated suppression of inflammation induced by DR3 signaling is dependent on Gal-9. J Immunol. 2017;199:2721-28.
- Wang Y, Song L, Sun J, Sui Y, Li D, Li G, et al. Expression of Galectin-9 and correlation with disease activity and vascular endothelial growth factor in rheumatoid arthritis. Clin Exp Rheumatol. 2020;38:654-61.
- Seki M, Oomizu S, Sakata KM, Sakata A, Arikawa T, Watanabe K et al. Galectin-9 suppresses the generation of Th17, promotes the induction of regulatory T cells, and regulates experimental autoimmune arthritis. Clin Immunol. 2008;127:78e88.
- Chou FC, Chen HY, Kuo CC, Sytwu HK. Role of galectins in tumors and in clinical immunotherapy. Int J Mol Sci. 2018;19:430.
- Lv Y, Ma X, Ma Y, Du Y, Feng J. A new emerging target in cancer immunotherapy: Galectin-9 (LGALS9). Genes Dis. 2022 Jun 4;10:2366-82.
- Fujita K, Iwama H, Oura K, Tadokoro T, Samukawa E, Sakamoto T et al. Cancer therapy due to apoptosis: Gal-9. Int J Mol Sci. 2017;18:74.
- Liu D, Zhu H, Li C. Galectins and galectin-mediated autophagy regulation: new insights into targeted cancer therapy. Biomark Res. 2023;11:22.
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- McCarty KS Jr, Szabo E, Flowers JL, Cox EB, Leight GS, Miller L, et al. Use of a monoclonal anti-estrogen receptor antibody in the immunohistochemical evaluation of human tumors. Cancer Res. 1986;46:4244-48.
- Jafari SM, Nazri A, Shabani M, Balajam NZ, Aghaei M. Gal-9 induces apoptosis in OVCAR-3 ovarian cancer cell through mitochondrial pathway. Res Pharm Sci. 2018;13:557-65
- Nobumoto A, Nagahara K, Oomizu S, Katoh S, Nishi N, Takeshita K et al. Gal-9 suppresses tumor metastasis by blocking adhesion to endothelium and extracellular matrices. Glycobiology. 2008;18:735-44.
- Nagahara K, Arikawa T, Oomizu S, Kontani K, Nobumoto A, Tateno H et a. Gal-9 increases Tim-3+ dendritic cells and CD8+ T cells and enhances antitumor immunity via galectin-9-Tim-3 interactions. J Immunol. 2008;181:7660-69.
- Nobumoto A, Oomizu S, Arikawa T, Katoh S, Nagahara K, Miyake M et al. Gal-9 expands unique macrophages exhibiting plasmacytoid dendritic cell-like phenotypes that activate NK cells in tumor-bearing mice. Clin Immunol. 2009;130:322-30.
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Meningiomlarda bağışıklık kontrol noktası molekülü Galektin-9'un immünohistokimyasal analizi
Year 2024,
Volume: 49 Issue: 3, 600 - 606, 30.09.2024
Ismail Saygin
,
Emel Çakır
,
Seher Nazlı Kazaz
,
Ali Rıza Güvercin
,
İlker Eyüboğlu
,
Müşerref Müge Ustaoğlu
Abstract
Amaç: Meningiom vakalarının çoğu cerrahi rezeksiyonla tedavi edilebilir. Ancak lezyonun lokalizasyonuna bağlı olarak tam çıkarılamayan veya yüksek dereceli meningiomların prognozu kötü olabilir. İmmünoterapi gibi yeni yöntemler, meningiomun hastaya özel, etkili tedavisine yönelik kapasitemizi artırabilir. Bu çalışmayla meningiomlarda Gal-9'un durumunu araştırarak kişiye özel yeni tedavi seçeneklerinin geliştirilmesine katkıda bulunmayı amaçlıyoruz.
Gereç ve Yöntem: Çalışmada 2007-2020 yılları arasında laboratuvarımızda tanısı konulan 402 olgu kullanıldı. İmmünhistokimya için doku mikroarray yöntemiyle birden fazla doku içeren yeni bloklar hazırlandı. Gal-9 antikorunun immünohistokimyasal boyanması H skoru yöntemi ile değerlendirildi.
Bulgular: Çalışmaya alınan 402 olgunun 289'u kadın, 113'ü erkekti. İki yüz yetmiş bir (%67,4) vaka WHO derece 1 idi; 121'i (%30,1) derece 2, 10'u (%2,5) derece 3 idi. Derece 1 ve 2 tümörlerde yüksek H skoru (sırasıyla 93,38 - 93,91), derece 3 tümörlerde ise düşük H skoru (59,40) gözlendi. Beyin invazyonu ile Gal-9 ekspresyonu arasında anlamlı bir ilişki yoktu. Gal-9 ekspresyonu ile tümör derecelendirmesinde kullanılan minör kriterler arasında anlamlı bir korelasyon bulunamadı.
Sonuç: Gal-9 H skoru ile tümör derecesi arasında istatistiksel olarak anlamlı fark gözlendi. Gal-9, yüksek dereceli meningiomlarda daha düşük bir H skoru gösterdi ve ekspresyon seviyeleri azaldı. Bu nedenle farklı ekspresyon seviyelerine sahip Gal-9, prognostik ve prediktif bir biyobelirteç olarak kullanılabileceği gibi tedavi için de önemli bir molekül olarak kullanılabileceği öngörülebilir.
Supporting Institution
TÜBİTAK, Project no: 220S403
References
- Ostrom QT, Gittleman H, Fulop J, Liu M, Blanda R, Kromer C et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008-2012. Neuro Oncol. 2015;17:iv1-62.
- Al-Rashed M, Foshay K, Abedalthagafi M. Recent advances in meningioma immunogenetics. Front Oncol. 2020;9:1472.
- Moar P, Tandon R. Gal-9 as a biomarker of disease severity. Cell Immunol. 2021;361:104287.
- Torp SH, Solheim O, Skjulsvik AJ. The WHO 2021 Classification of central nervous system tumours: a practical update on what neurosurgeons need to know-a minireview. Acta Neurochir (Wien). 2022;164:2453-64.
- Gupta S, Bi WL, Dunn IF. Medical management of meningioma in the era of precision medicine. Neurosurg Focus. 2018;44:E3.
- Shahbandi A, Shah DS, Hadley CC, Patel AJ. The role of pharmacotherapy in treatment of meningioma: a systematic review. Cancers. 2023;12;15:483.
- Foy SP. Mandl SJ. Dela Cruz T et al. Poxvirus-based active immunotherapy synergizes with CTLA-4 blockade to increase survival in a murine tumor model by improving the magnitude and quality of cytotoxic T cells. Cancer Immunol Immunother. 2016;65:537‐49.
- Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T et al. Check point blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature. 2014;515:577‐81.
- Yang R, Sun L, Li CF, Wang YH, Xia W, Liu B et al. Development and characterization of anti-gal-9 antibodies that protect T cells from galectin-9-induced cell death. J Biol Chem. 2022;298:101821.
- Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ et al. The Tim-3 ligand gal-9 negatively regulates T helper type 1 immunity. Nat Immunol. 2005;6:1245-52.
- Liu Z, Han H, He X, Li S, Wu C, Yu C et al. Expression of the gal-9 Tim-3 pathway in glioma tissues is associated with the clinical manifestations of glioma. Oncol Lett. 2016;11:1829-34.
- Daley D, Mani VR, Mohan N, Akkad N, Ochi A, Heindel DW et al. Dectin 1 activation on macrophages by gal-9 promotes pancreatic carcinoma and peritumoral immune tolerance. Nat Med. 2017;23:556-67.
- Wu C, Thalhamer T, Franca RF, Xiao S, Wang C, Hotta C et al. Gal-9 - CD44 interaction enhances stability and function of adaptive regulatory T cells. Immunity. 2014;41:270-82.
- Madireddi S, Eun SY, Mehta AK, Birta A, Zajonc DM, Niki T et al. Regulatory t cell-mediated suppression of inflammation induced by DR3 signaling is dependent on Gal-9. J Immunol. 2017;199:2721-28.
- Wang Y, Song L, Sun J, Sui Y, Li D, Li G, et al. Expression of Galectin-9 and correlation with disease activity and vascular endothelial growth factor in rheumatoid arthritis. Clin Exp Rheumatol. 2020;38:654-61.
- Seki M, Oomizu S, Sakata KM, Sakata A, Arikawa T, Watanabe K et al. Galectin-9 suppresses the generation of Th17, promotes the induction of regulatory T cells, and regulates experimental autoimmune arthritis. Clin Immunol. 2008;127:78e88.
- Chou FC, Chen HY, Kuo CC, Sytwu HK. Role of galectins in tumors and in clinical immunotherapy. Int J Mol Sci. 2018;19:430.
- Lv Y, Ma X, Ma Y, Du Y, Feng J. A new emerging target in cancer immunotherapy: Galectin-9 (LGALS9). Genes Dis. 2022 Jun 4;10:2366-82.
- Fujita K, Iwama H, Oura K, Tadokoro T, Samukawa E, Sakamoto T et al. Cancer therapy due to apoptosis: Gal-9. Int J Mol Sci. 2017;18:74.
- Liu D, Zhu H, Li C. Galectins and galectin-mediated autophagy regulation: new insights into targeted cancer therapy. Biomark Res. 2023;11:22.
- Wdowiak K, Francuz T, Gallego-Colon E, Ruiz-Agamez N, Kubeczko M, Grochoła I et al. Galectin targeted therapy in oncology: current knowledge and perspectives. Int J Mol Sci. 2018;19:210.
- Fujihara S, Mori H, Kobara H, Rafiq K, Niki T, Hirashima M et al. Gal-9 in cancer therapy. Recent Pat Endocr Metab Immune Drug Discov. 2013;7:130-7.
- McCarty KS Jr, Miller LS, Cox EB, Konrath J, McCarty KS Sr. Estrogen receptor analyses. Correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies. Arch Pathol Lab Med. 1985;109:716-21.
- Rakha EA, Soria D, Green AR, Lemetre C, Powe DG, Nolan CC, et al. Nottingham Prognostic Index Plus (NPI+): a modern clinical decision making tool in breast cancer. Br J Cancer. 2014;110:1688-97.
- McCarty KS Jr, Szabo E, Flowers JL, Cox EB, Leight GS, Miller L, et al. Use of a monoclonal anti-estrogen receptor antibody in the immunohistochemical evaluation of human tumors. Cancer Res. 1986;46:4244-48.
- Jafari SM, Nazri A, Shabani M, Balajam NZ, Aghaei M. Gal-9 induces apoptosis in OVCAR-3 ovarian cancer cell through mitochondrial pathway. Res Pharm Sci. 2018;13:557-65
- Nobumoto A, Nagahara K, Oomizu S, Katoh S, Nishi N, Takeshita K et al. Gal-9 suppresses tumor metastasis by blocking adhesion to endothelium and extracellular matrices. Glycobiology. 2008;18:735-44.
- Nagahara K, Arikawa T, Oomizu S, Kontani K, Nobumoto A, Tateno H et a. Gal-9 increases Tim-3+ dendritic cells and CD8+ T cells and enhances antitumor immunity via galectin-9-Tim-3 interactions. J Immunol. 2008;181:7660-69.
- Nobumoto A, Oomizu S, Arikawa T, Katoh S, Nagahara K, Miyake M et al. Gal-9 expands unique macrophages exhibiting plasmacytoid dendritic cell-like phenotypes that activate NK cells in tumor-bearing mice. Clin Immunol. 2009;130:322-30.
- Zhou X, Sun L, Jing D, Xu G, Zhang J, Lin L et al. Gal-9 expression predicts favorable clinical outcome in solid tumors: a systematic review and meta-analysis. Front Physiol. 2018;9:452